The invention is further described by way of examples herein. It should be noted that the examples have an exemplary and illustrative nature and the description of the invention involves the whole teaching provided herein. Experiments were carried out on male Wistar rats Charles River weighing g received from the breeding colony of Semmelweis University.
Room temperature and relative humidity was checked daily. The rats were maintained on standard laboratory chow and tap water ad libitum. All procedures conformed to the European Convention for the protection of vertebrate animals used for experimental and other scientific purposes. In a modified version of the shuttle box the acquisition of a two-way conditioned avoidance reflex CAR was analyzed during 5 consecutive days.
The rat was put in a box divided inside into two parts by a barrier with a small gate in the middle, and the animal was trained to cross the barrier under the influence of a conditioned stimulus CS, light flash. If it failed to respond within 5s, it was punished with a foot-shock 1mA , the unconditioned stimulus US. If the rat failed to respond within 5s to the US, it was classified as an escape failure EF.
One trial consisted of 10s intertrial interval, followed by 20s CS. The last 5s of CS overlaped the 5s US. Due to the weak performance of the catecholaminergic brain engine, the activation of the cortical neurons remains below the level required for the acquisition of a CAR. The enhancer substances exert their enhancer effect with a peculiar dose-dependency: a bi-modal, bell- shaped concentration effect curve is characteristic to the enhancer effect.
Mammalian instincts must be understood to be managed.
We selected for the longevity study two doses of Deprenyl, 0. The 0. Regarding the dose with the non-specific enhancer effect, the less effective 0. For the longevity study we selected the optimal dose that elicited the specific 0. The fact that 0. In optimally low doses of PEA and Deprenyl, as well as, tryptamine and BPAP, there is an increase in the excitability of enhancer-sensitive neurons, thus we measured the enhancement of the impulse propagation mediated release of the transmitters from the catecholaminergic and the serotonergic neurons in the brain.
In low doses Deprenyl is a selective CAE- substance. The longevity study was performed on male rats received from the breeding colony of the Semmelweis University. The rats were born at the end of February of After 2-month acclimation period the rats were divided randomly into 5 even groups.
The longevity study started at the beginning of May Animals were observed until their natural deaths. The data in this study represent the changes observed until October 31, , since in the saline-treated group the last animal died on October 31, As will be shown later a few rats in the enhancer-treated groups were still alive on November 1, During the longevity study 5 rats were housed together in polycarbonate cages height: 18 cm; wide: 42 cm; length: 44 cm with a stainless steel on the top. Cage bedding was renewed 3 times a week Monday, Wednesday and Friday.
Bodyweight was measured once every month. The treatment started at the end of the second month of their age. The treatment of the five groups of rats participating in the longevity study is shown in Table 3. To avoid the mixing of the groups and individuals, saline-treated rats were signed blue froml to 40; D-treated rats were signed green from 1 to 80 rats treated with 0.
Table 3. Treatment on Wistar male rats participating in the longevity study. We carefully observed the appearance of the subcutaneous tumor and followed the development of the tumor until death. Histological analysis was performed post mortem on several rats taken from each group as examples.
The subcutaneous tumors developed in the rats were measured by the two largest diameters.
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After sacrificing the animals, the tumors were removed, photographs were taken. The tumors were white-greyish, of soft consistency. Occasionally hemorrhagic and necrotic areas of various degree could be detected. Histologically the tumor cells were round or elongated with roundish or oval nuclei and eosinophilic cytoplasm.
Occasionally mitotic figures were seen. The cells were embedded in a pale partly eosinophilic, partly basophilic loose matrix which contained areas of collagen fibers. The tumor infiltrated the subcutaneous tissues and the striated muscles. To prove the origin of the tumors, immunohistochemical reactions were carried out on formalin-fixed, paraffin embedded sections.
Following deparaffinization and rehydrations the slides were incubated by the following primary antibodies against vimentin Dako, Glostrup, Denmark, 1 : dilution , smooth muscle antibodies SMA, Dako, dilution , desmin Dako, dilution , Ki67 Dako, 1: dilution. Immunohistochemistry proved the mesenchymal origin of the tumor cells, which stained strongly with vimentin, however reactions for SMA and desmin were negative.
The final histological diagnosis was fibromyxosarcoma in the subcutaneous tissue. The lifespan prolonging effect of low doses of Deprenyl andBPAP in which they exert their "specific" and "non-specific" enhancer effect.
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In our two longevity studies with Deprenyl performed before the discovery of the CAE effect of the drug, we used the 0. In this study, we used the peak doses of Deprenyl in which the compound exerted in the Shuttle box experiment its "non-specific" and "specific" enhancer effect see Fig. The first animal in the saline-treated group died in the 9 th month of its age and the last animal died in the 32 nd month of its age. Though according to Fig. B-treated rats lived, however, significantly longer than their saline-treated peers. In the course of our longevity study we discovered that a peculiar, previously unknown enhancer- sensitive TMS mechanism is operating in the brain of our rats.
It belongs to the natural endowments of the Wistar rats Charles River that around the completion of the first year of their life a rapidly growing fibromyxosarcoma, infiltrating the subcutaneous tissue including the muscles, starts to appear, the number of tumor manifesting rats is increasing with the passing of time, and finally about half of the population dies with the fibromyxosarcoma.
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In our running longevity study the first animal manifested the tumor in the saline-treated group of rats during the 11 th month of age and 20 rats in the group manifested the tumor to the end of 27 th month of their age. The last two animals in this group died during the 32 nd month. In the group of rats treated with 0. The last animal manifested the tumor during the 32 nd month. Two rats in this group are still alive. The last animal manifested the tumor during the 29 th month.
The last animal in this group died during the 32 nd month of its age. The last animal manifested the tumor during the 29 th month of its age. Five rats in this group are still alive.
The last animal manifested the tumor during the 31 st month. One rat in this group is still alive. Firm tumors appeared in subcutaneous localization in the rats. Photos have been made to illustrate the typical subcutaneous localization of the fibrosarcomas. The tumors were well circumscribed, however, no detectable capsule could be seen. Photos have been made to illustrate the cut surface of the tumors was greyish-white, with no specific structures. Occasionally small hemorrhagic areas and yellow homogeneous necrotic areas could be seen. On hematoxylin-eosin HE stained section, the tumor cells were located in a loosely arranged pale, eosinophilic matrix with large number of small vessels.
The tumor cells had elongated or stellate forms with centrally or excentrically located roundish nuclei and pale eosinophilic cytoplasm. Occasionally mitotic figures were detected. On PAS reaction, the matrix gave a pale positive reaction, the tumor cells were mainly negative. Photos have been made to show the typical histology of the subcutaneous tumors. By immunohistochemical reaction, the tumor cells stained strongly positive for vimentin. Antibody for SMA smooth muscle antigen stained only the vessels, the tumor cells were negative.
Anti-desmin antibodies reacted with muscle components only which were infiltrated by the negatively stained tumor cells. The data furnish experimental evidence that with the passing of time a continuosly increasing percentage of the Wistar rats used in our study develop a rapidly growing subcutaneous fibromyxosarcoma and it seems evident that the manifestation of this tumor belongs to the natural endowments of this strain.
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First, both cell lines were treated by - -BPAP and - -deprenil in monotherapy to determine its dose-effect curves in concentration of 10 "6 , 10 "7 , 10 "8 , 10 "9 , 10 "10 , 10 "11 , 10 "12 , 10 "13 and 10 "14 M. In combined treatment 10 "3 , 3. Cell proliferation was evaluated by MTT 3- 4,5-Dimethylthiazolyl -2,5-diphenyltetrazolium bromide assay M, Sigma after hour treatment by the method described in manufacturer's protocol.
Significance in the performance between the groups in the shuttle box was evaluated by multi-factor analysis of variance ANOVA. Significance regarding the span of time from tumor manifestation until death in rats and regarding aging related changes in bodyweight treated chronically with the enhancer substances was analyzed by One-way ANOVA. Statistical analysis of survival rate and tumor manifestation was performed by the Kaplan-Meier method. We tested the effect of the enhancer substances in two types of human cultured medulloblastoma cell lines: Daoy HTB cell line, originating from desmoplastic cerebellar medulloblastoma Jacobsen et al.
In none of the applied concentrations did Deprenyl or BPAP influence the proliferation on the cultured medulloblastoma cells. Moreover, BPAP and Deprenyl did not change the effectiveness of the investigated well-known tumor-cell proliferation inhibiting agents see the investigated combinations in Methods.
The ineffectiveness of the enhancer substances on the proliferation of cultured tumor cells is congruent with the physiological function of the enhancer-sensitive TMS regulation. To examine the effect of - -deprenyl and - -BPAP on the lifespan of mice and autopsy made on randomly selected mice treated with doses in which they exert their "specific" low, i. Five groups of mice are treated daily from sexual maturity with two different doses of.
A total of mice entered the experiments. Body weight is measured bimonthly. For monitoring, we planned to sacrifice mice from each group at 6-month, 1-year, 1. The longevity study is still running; until the time being November, the autopsy has been made of the 6-month, 1-year, 1. No lung carcinoma was detected in the 6-month or 1-year saline- treated mice.
The results are shown in Table 4 and on Figures 19 and Significance levels were calculated with two- sided Chi-square test. Table 4. Results of the autopsy of mice after month daily treatment with saline and enhancer substances, respectively. Table 4 shows that none of the 18 months old dissected mice, treated with specific enhancer dose, have developed lung carcinoma. This measurement can be made, mutatis mutandis, analogously to the measurement described in example 2 of EPB1 corresponding to WOA1.
In short the brain stem average weight about mg is isolated from rats and soaked in oxygenated Krebs' solution. Then solution of labelled neurotransmitter the release of which is measured is added to the preparation and allowed for uptake in an appropriate environment. If needed, MAO activity is inhibited. After uptake of the monoamine the brain stem is fixed in appropriate organ bath and washed in appropriate solution facilitating uptake and preventing metabolization of the monoamine.
Fractionation of the perfusate is carried out periodically and, if the monoamine is radiolabeled, fractions are combined with a scintillation liquid. The compound s of the invention are solved in perfusate buffer at enhancer concentration. As a negative control, the perfusate buffer or an appropriate buffer not comprising the compound can be used. As a positive control a compound with a known enhancer effect can be used. If the curve typical of enhancer effect typically a bimodal curve is to be taken solutions of different concentrations spanning the possible concentration ranges are prepared.
The organ is perfused with the buffer containing the compound s of the invention for sufficient time before electrostimulation. The brain stem is stimulated with rectangular pulses e. Thereafter it is allotted several, e. The compound of the invention is confirmed to enhance the monoamine neurotransmitter release by the increase of the exocytosis, when electrostimulation was given to the neuronal cells. If a low dose or a minimum dose of the compound of the invention, causing release of the monoamine neurotransmitter from the electric -stimulated brain e.
If a concentration series spanning a range is applied, typically a bimodal curve of released monoamine amounts, as a function of the concentration of the inventive compound, is obtained. However, at least a bell- shaped curve is obtained in a low concentration range typical of the enhancer effect.
Typically the medium of this curve is below 0. This measurement can be made, mutatis mutandis, analogously to the measurement described in example 4 of EPB1 corresponding to WOA1. Brain tissues such as striatum, substantia nigra, tuberculum olfactorium, locus coeruleus and raphe isolated from rats, e. Wistar rats are soaked in oxygenated Krebs' solution at body temperature. The preparations are submerged in organ bath, incubated for appropriate time, the solution is exchanged as and when needed. After the tissue s is are submerged for appropriate time in Krebs' solution containing the compounds of the invention, the biogenic amine released during this period is quantified.
The compound s of the invention, if appropriate, a positve control which is a known enhancer compound are dissolved in saline, as well as saline as a negative control, are subcutaneously administered 30 min before dissection of brain samples. The amount of appropriate amine released for 20 min is measured, e. The differences among means are tested e. Significance level is set e. It is expected that an enhancer compound increases monoamine neurotransmitter release.
In particular a pure enhancer compound increases monoamine neurotransmitter release in a low concentration, e. The peculiar mechanism of action of the proper low specific enhancer doses of the enhancer substances forms the basis of their unique safety. In the extremely low dose in which they exert their specific enhancer effect, they selectively transform the lower performing enhancer sensitive neurons to better performing ones.
Since a bi-modal, bell-shaped concentration effect curve is characteristic to the enhancer effect, a given concentration range typical of the specific enhancer effect of the enhancer substance was needed for the appropriate performance, and both a lower and a higher concentration were less effective. Lifelong preventive medication requires unique drug safeness. All drugs used today harshly change the physiological milieu of the highly sophisticated living material, so they are, in principle, incompatible for lifelong daily administration.
In contrast, the synthetic enhancer substances of the present invention, in particular in the low concentration in which they exert their specific enhancer effect, transform the lower performing enhancer-sensitive neurons for better performing ones - leaving the physiological milieu of the neurons unchanged - are suitable for lifelong preventive medication. The enhancer substances, e. Deprenyl or PPAP of the present invention exert their specific enhancer effect in a very low dose.
As typically, as exemplified by Deprenyl, they are tolerated in a higher dose, the savety margin of these compounds are unique. The discovery of a previously unknown mechanism by the present inventors, a tumor-manifestation-suppressing TMS regulation in the mammalian brain, is an example for previously unknown enhancer-sensitive brain regulation. The present inventors disclose herein the first time a tumor suppression mechanism based on the catecholaminergic specific enhancer activity of a syntetic phenylethylamine analog compounds. The present results show that enhancer substances of the present invention increase the activity of the catecholaminergic neurons qualitatively differently from any of the drugs used for this purpose today.
The invention relates to pharmaceutical preparations, in particular medicaments for use in the prevention and treatment of cancer, in particular suppression of tumor manifestation as well as methods for the same. Ahmed H, Shah N. Neurobiol Aging, 3 A new low-dose formulation of selegiline: clinical efficacy, patient preference and selectivity for MAO-B inhibition.
Acta Physiologica Hungarica Fowler, Joanna S. Neuropsychopharmacology advance online publication, published on-line; doi: J Neural Transm Suppl. J Neuropathol Exp Neurol Neurochem Res Oncol Res Further evidence. Life Sci Knoll J The striatal dopamine dependency of life span in male rats.
Longevity study with - deprenyl. Mech Ageing Dev Knoll J Memories of my 45 years in research. Pharmacol Toxicol Knoll J Antiaging compounds: - Deprenyl Selegiline and - l- benzofuranyl propylaminopentane, - BPAP, a selective highly potent enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain. CNS Drug Rev Berlin, Heidelberg, New York: Springer; p.
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Show all. Table of contents 7 chapters Table of contents 7 chapters Introduction Pages Innate and Acquired Drives Pages Conclusion Pages